Abstract: Non-alcoholic steatohepatitis (NASH) is a relatively common disorder characterized by the presence of fat in the liver accompanied by inflammatory changes (infiltration with polymorphonuclear cells, presence of Mallory bodies, hepatocyte necrosis, and in some cases fibrosis or cirrhosis). Earlier studies have recognized a relationship of NASH to obesity and diabetes, as well as to the toxicity of several drugs. However, virtually nothing is known of it pathophysiology, and thus rational therapy, aide from the treatment of obesity and diabetes, and discontinuation of offending drugs, is not yet possible. We propose that NASH is a final pathological response to a number of insults to the liver that result in elevated liver free fatty acid levels. This leads to triglyceride accumulation, which in turn renders the liver in some individuals more sensitive to lipid peroxidation or to endotoxinemia (or other activators of cytokine cascades). We will gain information about the pathophysiology of this disease by comparing liver biopsy-proven NASH patients with controls matched for age, gender, race, and presence of diabetes for metabolic fuel usage, insulin sensitivity, activation of cytokine pathways, lipid peroxidation, and body fat distribution. The results of this study should point to important metabolic differences between controls and NASH patients, suggesting risk factors that can be modified and leading to trials of therapy aimed at correcting the abnormalities defined.